Abstract
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can selectively kill neoplastic cells and control of its activity could enhance tumor therapy. We have developed means to control the secretion of a novel recombinant (r) TRAIL fusion protein using a viral protease. This system uses the endoplasmic reticulum (ER) as a storage depot for rTRAIL, because TRAIL acts by binding to its cognate receptors on the cell surface. We have engineered two TRAIL variants: (a) a secretable form that enhances apoptosis via a bystander effect; and (b) an ER-targeted TRAIL that is retained in the ER until selectively released by the viral protease. Gene delivery can be monitored in vivo by systemic administration of a near infrared fluorescent (NIRF) probe activated by the protease. This study serves as a template for design of recombinant proteins to enhance and control apoptosis of tumor cells via specific viral proteases and for use of viral proteases as in vivo reporters for cancer therapy.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Apoptosis / physiology
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Apoptosis Regulatory Proteins
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Chlorocebus aethiops
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Endopeptidases / biosynthesis
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Endopeptidases / genetics
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Endopeptidases / metabolism
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Endoplasmic Reticulum / metabolism
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Glioma / genetics
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Glioma / metabolism
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Glioma / therapy
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Herpesvirus 1, Human / enzymology
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Herpesvirus 1, Human / genetics
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Membrane Glycoproteins / administration & dosage
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Nude
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Recombinant Fusion Proteins / administration & dosage*
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / physiology
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Spectroscopy, Near-Infrared
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TNF-Related Apoptosis-Inducing Ligand
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Tumor Necrosis Factor-alpha / administration & dosage
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Tumor Necrosis Factor-alpha / genetics
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Tumor Necrosis Factor-alpha / metabolism*
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Vero Cells
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Viral Proteins / biosynthesis
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Viral Proteins / genetics
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Viral Proteins / metabolism
Substances
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Apoptosis Regulatory Proteins
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Membrane Glycoproteins
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Recombinant Fusion Proteins
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TNF-Related Apoptosis-Inducing Ligand
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TNFSF10 protein, human
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Tnfsf10 protein, mouse
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Tumor Necrosis Factor-alpha
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Viral Proteins
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Endopeptidases